OP0291 ACUTE PHASE REACTANT OROSOMUCOID-2 DIRECTLY PROMOTES RHEUMATOID INFLAMMATION
Authors: K. M. Kim, S. Lee, K. G. Lee, B. K. Hong, Y. J. Park, S. A. Yoo, W. U. Kim
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Acute phase response is a systematic reaction of organisms. It occurs when the homeostasis of our body is broken by infection, tissue injury, and inflammation. Since most of these acute phase reactants can be rapidly secreted to the blood in response to infection or inflammation, they have been utilized as serum diagnostic markers to predict the activity and outcomes of chronic inflammatory diseases. In recent years, evidence has emerged that some of these acute phase reactants can go beyond simply being useful as diagnostic markers. Studies have shown that they can directly function as immune modulators. <h3>Objectives</h3> To determine whether orsomucoid-2 (ORM2), an acute phase reactant mainly synthesized in the liver, directly contributes to chronic inflammation. <h3>Methods</h3> ORM2 expression was determined by ELISA and immunostaining. Fibroblast-like synoviocytes (FLSs) and macrophages were cultured in the presence of recombinant ORM2. NF-κB and p38 MAP kinase expression levels were assessed by Western blot analysis. Knockdown experiments were carried out using siRNAs for NF-κB p65, p38, and glycophorin C (GYPC). Proximity ligation assay was performed to test the molecular interaction between ORM2 and GYPC. Recombinant ORM2 was injected into the affected joints of mice with IL-1β-induced arthritis. <h3>Results</h3> ORM2 expression was elevated in the sera, synovial fluids, and synovia of patients with rheumatoid arthritis (RA). Major cell types producing ORM2 were synovial macrophages and FLSs. Recombinant ORM2 robustly upregulated IL-6, TNF-α, IL-8, and CCL2 produced by macrophages and/or FLSs of RA patients via NF-κB and p38 MAPK pathways. GYPC was the receptor of ORM2 on synovial macrophages and FLSs. Such an increase by ORM2 was reproduced in mouse macrophages and FLSs. Intra-articular injection of ORM2 promoted the severity of arthritis in mice and accelerated the infiltration of macrophages in affected joints. Moreover, in RA patients, circulating ORM2 levels correlated with disease activity assessed by DAS28 and well represented radiographic progression in 2 years. <h3>Conclusion</h3> Acute phase protein ORM2 can directly increase the production of pro-inflammatory cytokines/chemokines by macrophages and FLSs and promote chronic arthritis in mice, suggesting that it could be a new therapeutic target for RA. <h3>References</h3> [1]Moshage H. Cytokines and the hepatic acute phase response. <i>J Pathol</i> 997;181(3):257-66. [2]Rodriguez W, Mold C, Marnell LL, et al. Prevention and reversal of nephritis in MRL/lpr mice with a single injection of C-reactive protein. <i>Arthritis Rheum</i> 2006;54(1):325-35. [3]Firestein GS, McInnes IB. Immunopathogenesis of Rheumatoid Arthritis. <i>Immunity</i> 2017;46(2):183-96. [4]Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. <i>Immunol Rev</i> 2010;233(1):233-55. [5]Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. <i>Nat Rev Rheumatol</i> 2013;9(1):24-33. <h3>Acknowledgements</h3> This study was supported by grants (NRF-2015R1A3A2032927 and NRF-2019R1A2C2010897) from the National Research Foundation (NRF) funded by the Ministry of Education, Science, and Technology, Republic of Korea. <h3>Disclosure of Interests</h3> None Declared.